A Novel Pharmacological Inhibitor of Adenylyl Cyclase Type 5 to Treat Alzheimer's Disease - Project Summary: Alzheimer’s Disease is associated with metabolic dysfunction, glucose and insulin resistance, oxidative stress, mitochondrial dysfunction, and reduced exercise capacity. Oxidative stress and mitochondrial dysfunction correlate with the development of beta-amyloid (Aβ) deposits, one of the hallmarks of AD that begin years before the onset of memory and cognitive decline. Moreover, patients with AD have a reduced lifespan. Accordingly, it would be beneficial to examine novel models of healthful longevity with enhanced metabolism, glucose and insulin tolerance, exercise capacity, and protection against oxidative stress, mitochondrial dysfunction, and apoptosis. All these features are present in the adenylyl cyclase type 5 (AC5) knock out (KO) mouse, which exhibits healthful longevity, associated with all major molecular factors that protect against AD. Adenylyl cyclase (AC) induces cyclic AMP (cAMP) and, therefore, regulates sympathetic control and β-adrenergic receptor (β- AR) signaling, and is thus a key regulator of health and longevity in organisms ranging from yeast to mammals. AC5 is one of ten AC isoforms and is expressed in virtually every organ in the body, including the brain. In support of its role in aging, we have found that disruption of AC5 (AC5 KO) promotes healthful longevity, enhances exercise performance and protects against diabetes and heart failure, all of which should be helpful in protecting against Alzheimer’s Disease. Our preliminary data also show that AC5 KO mice perform better on memory and motor tasks compared to wild-type mice. In contrast, the Alzheimer model J20 mice, a transgenic animal that overexpresses mutant human amyloid precursor protein (APP), exhibits memory loss as expected. A pharmacological inhibitor of AC5 is the goal for clinical translation. We have developed a pharmacological inhibitor of AC5, which is known as C90, as the lead candidate for the inhibition of AC5 targeting myocardial ischemia. C90 leads to robust inhibition of AC5, has high solubility and readily absorbed orally. It showed efficacy in animal models of exercise and myocardial ischemia. The main drawback with C90 is the presence of a hydroxamic acid group. Hydroxamates are associated with adverse effects and are often mutagenic. The mutagenicity of the hydroxamate group is proposed be due to its rearrangement to isocyanate which act as alkylating agents of DNA. The goal of this application is to design and synthesize a novel C90 that would retain the biological activity of C90, but devoid of the toxic liability of a hydroxamic acid group.
